This is a new 3-year R01 application involving a Cancer Therapy Evaluation Program of the National Cancer Institute (NCI/CTEP) awarded phase II study of the Akt inhibitor MK-2206 in patients with progressive, recurrent/metastatic adenoid cystic carcinomas (R/M ACCs). This will be a national study conducted through the Alliance for Clinical Trials in Oncology cooperative group mechanism. ACC is one of the most common histologic subtypes of salivary cancers, and R/M ACC is an incurable disease with no standard treatments. New therapies are urgently needed for this patient population. The recent discovery of a unique t(6;9) translocation in a significant proportion of ACC tumors has provided a primary genetic driver of ACC tumorigenesis at which therapeutic strategies may now be directed. Specifically, the translocation involves the creation of a fusion gene (MYB-NFIB) that results in the marked overexpression of c-myb, an oncogenic transcription factor that activates a transcriptional program critical to the biology of several malignancies. While over 70% of all ACCs overexpress MYB, it is virtually undetectable in either normal salivary tissue or other salivary cancers. Without validated ACC experimental models with which to explore strategies for MYB targeting, we developed a cell line model expressing either full-length MYB or the MYB-NFIB fusion and discovered that Akt inhibition with the allosteric small molecule inhibitor MK-2206 (Merck) effectively downregulates c-myb levels. We hypothesized that this would be a novel strategy for clinically targeting c-myb in ACC. In collaboration with CTEP, we have developed a phase II clinical trial evaluating MK-2206 in patients with progressive, R/M ACC based upon this hypothesis. In this application, we propose to evaluate the clinical efficacy of MK-2206 in the treatment of ACC patients (Specific Aim #1), explore potential molecular and pathologic predictors of objective response to MK-2206 (Specific Aim #2), and analyze pre- and post-MK- 2206 treatment biopsies in order to test our preclinical hypothesis that MK-2206 inhibition of Akt in ACC tumors translates to clinical responses (Specific Aim #3). Such work will not only guide the development of future ACC studies, but will also validate c-myb overexpression as a marker of tumor susceptibility to Akt targeting strategies that can be applied to other cancers that overexpress MYB.